Clinical implications of fracture severity risk with pioglitazone: A systematic review and meta-analysis of clinical randomized trials

Hala Azhari ^1* Jesse Dawson ²

• ¹ Umm al-Qura University, Mecca, Saudi Arabia
• ² University of Glasgow, Glasgow, Scotland, United Kingdom

Introduction: Pioglitazone, a thiazolidinedione, effectively reduces stroke and cardiovascular events in individuals with type 2 diabetes, insulin resistance, and stroke. However, its potential to increase fracture risk, particularly among females and those with pre-existing skeletal conditions, remains a concern. This meta-analysis aims to clarify fracture risk associated with pioglitazone, focusing on individuals with a history of stroke. Methods: A systematic review of clinical trials was conducted up to March 2024, focusing on trials comparing pioglitazone to placebo or other antihyperglycemic drugs that reported fracture outcomes. Results: From 860 trials identified, 78 satisfied the inclusion criteria: 34 with high risk of bias, 8 with unclear risk, and 36 with low risk. The meta-analysis revealed that pioglitazone is associated with a significant increase in fracture risk (risk ratio [RR] 1.21; 95% CI 1.01–1.45; P=0.04), including non-serious (RR 1.25; 95% CI 1.03–1.51; P=0.02) and serious fractures (RR 1.48; 95% CI 1.10–1.98; P=0.01). Notably, the risk was heightened for low-energy fractures, particularly from falls (RR 1.49; 95% CI 1.20–1.87; P=0.0004), in insulin resistance individuals (RR 0.87; 95% CI 0.43–1.76; P=0.69) and stroke survivors (RR 1.41; 95% CI 1.09–1.83; P=0.008). Fractures were most frequently observed in lower extremities (RR 1.85; 95% CI 1.33–2.56; P=0.0002), with females at greater risk (RR 1.56; 95% CI 1.20–2.02; P=0.0008). When compared with other antihyperglycemic drugs, no significant difference in fracture risk was noted (RR 1.08; 95% CI 0.73–1.59; P=0.70), except rosiglitazone, which showed higher fracture risk (RR 1.42; 95% CI 1.23–1.64; P<0.00001). Fracture risk was significant in the fixed-effect model but not in the random-effects model. Discussion: While pioglitazone offers cardiovascular benefits, its association with increased fracture risk—especially among females and nondiabetic individuals’ post-stroke—warrants careful consideration. Individualized treatment approaches balancing cardiovascular and skeletal outcomes are essential, and further research is needed to optimize therapeutic strategies in this population.